Regiocontrolled Halogen Dance and In Situ Transmetalation of Pyrroles Directed by the α-Substituent

Abstract

Multiply substituted pyrroles are found in medicines, natural products, and functional materials. A general method for introducing functionality on the pyrrole ring is thus required. Herein, a regiocontrolled halogen dance reaction and an in situ transmetalation of α-functionalized bromopyrroles are reported. Selective generation of the isomeric pyrrolylmetal species was achieved by using an ethyl ester or a phenyl group at the α-position of the pyrrole and by switching between the halogen dance reaction and in situ transmetalation. These reactions proceeded smoothly when an N,N-dimethylsulfamoyl group was attached to the pyrrole nitrogen atom, providing the corresponding products in 68% to quantitative yields on 1-mmol scale. This method was applicable to the formal synthesis of Kendine 91.

Key words

deprotonation - halogen dance - in situ transmetalation - organometallic reagents - pyrroles - regioselectivity

Publication History

Received: 09 December 2023

Accepted after revision: 28 December 2023

Accepted Manuscript online:
28 December 2023

Article published online:
22 February 2024

• References and Notes

• 1a Jeelan Basha N, Basavarajaiah SM, Shyamsunder K. Mol. Diversity 2022; 26: 2915
• 1b Fukuda T, Ishibashi F, Iwao M. The Alkaloids: Chemistry and Biology, Vol. 83. Knölker H.-J. Academic Press; San Diego: 2020: 1-112
• 1c Ding Y, Tang Y, Zhu W, Xie Y. Chem. Soc. Rev. 2015; 44: 1101
• 2 For a recent review, see: Philkhana SC, Badmus FO, Dos Reis IC, Kartika R. Synthesis 2021; 53: 1531

For selected recent examples, see:
• 3a Chiu H.-C, Tonks IA. Angew. Chem. Int. Ed. 2018; 57; 6090
• 3b Kondoh A, Iino A, Ishikawa S, Aoki T, Terada M. Chem. Eur. J. 2018; 24: 15246
• 3c Prabagar B, Mallick RK, Prasad R, Gandon V, Sahoo AK. Angew. Chem. Int. Ed. 2019; 58: 2365
• 3d Li J.-K, Zhou B, Tian Y.-C, Jia C, Xue X.-S, Zhang F.-G, Ma J.-A. Org. Lett. 2020; 22: 9585

For selected reviews, see:
• 4a Belen’kii LI, Kim TG, Suslov IA, Chuvylkin ND. Russ. Chem. Bull. 2005; 54: 853
• 4b Borah B, Dwivedi KD, Chowhan LR. Asian J. Org. Chem. 2021; 10: 2709

For selected examples via pyrrolyllithium species, see:
• 5a Banwell MG, Flynn BL, Hamel E, Hockless DC. R. Chem. Commun. 1997; 207
• 5b Fukuda T, Ohta T, Sudo E.-I, Iwao M. Org. Lett. 2010; 12: 2734

For selected reviews, see:
• 6a Bunnett JF. Acc. Chem. Res. 1972; 5: 139
• 6b Schnürch M, Spina M, Khan AF, Mihovilovic MD, Stanetty P. Chem. Soc. Rev. 2007; 36: 1046
• 6c Erb W, Mongin F. Tetrahedron 2016; 72: 4973
• 6d Inoue K, Okano K. Asian J. Org. Chem. 2020; 9: 1548
• 7a Kano S, Yuasa Y, Yokomatsu T, Shibuya S. Heterocycles 1983; 20: 2035
• 7b Fröhlich H, Kalt W. J. Org. Chem. 1990; 55: 2993
• 7c Okano K, Sunahara K, Yamane Y, Hayashi Y, Mori A. Chem. Eur. J. 2016; 22: 16450
• 8a Mari D, Miyagawa N, Okano K, Mori A. J. Org. Chem. 2018; 83: 14126
• 8b Kautny P, Lumpi D, Wang Y, Tissot A, Bintinger J, Horkel E, Stöger B, Hametner C, Hagemann H, Ma D, Fröhlich J. J. Mater. Chem. 2014; 2: 2069
• 8c Hosoya M, Mori A, Okano K. Synlett 2024; 35: 431
• 9a Liu JH, Yang QC, Mak TC, Wong HN. J. Org. Chem. 2000; 65: 3587
• 9b Jolicoeur B, Chapman EE, Thompson A, Lubell WD. Tetrahedron 2006; 62: 11531
• 10 Okumi T, Mori A, Okano K. Chem. Commun. 2023; 59: 1046

We have recently applied the halogen dance reaction of a 2,3-dibromopyrrole bearing an ester moiety to the total synthesis of lamellarins. There was no regioselectivity problem because there was only one hydrogen attached to the pyrrole. For more details, see:
• 11a Morikawa D, Morii K, Yasuda Y, Mori A, Okano K. J. Org. Chem. 2020; 85: 8603
• 11b Morii K, Yasuda Y, Morikawa D, Mori A, Okano K. J. Org. Chem. 2021; 86: 13388
• 11c Okui Y, Yasuda Y, Mori A, Okano K. Synthesis 2022; 54: 2647
• 11d Okui Y, Mori A, Okano K. Org. Lett. 2023; 25: 2669
• 12a L’Helgoual’c J.-M, Seggio A, Chevallier F, Yonehara M, Jeanneau E, Uchiyama M, Mongin F. J. Org. Chem. 2008; 73: 177
• 12b Frischmuth A, Fernández M, Barl NM, Achrainer F, Zipse H, Berionni G, Mayr H, Karaghiosoff K, Knochel P. Angew. Chem. Int. Ed. 2014; 53: 7928
• 12c Brikci-Nigassa NM, Bentabed-Ababsa G, Erb W, Mongin F. Synthesis 2018; 50: 3615
• 13a Inoue K, Feng Y, Mori A, Okano K. Chem. Eur. J. 2021; 27: 10267
• 13b Feng Y, Yukioka T, Matsuyama M, Mori A, Okano K. Org. Lett. 2023; 25: 3013
• 13c Inoue K, Mori A, Okano K. Org. Lett. 2023; 25: 6693
• 14 Typical procedure for the halogen dance reaction; Ethyl 3-bromo-1-(N,N-dimethylsulfamoyl)-1H-pyrrole-2-carboxylate (17b): A flame-dried 50-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with ethyl 5-bromo-1-(N,N-dimethylsulfamoyl)-1H-pyrrole-2-carboxylate (16b; 328.2 mg, 1.01 mmol, 1.0 equiv) and THF (10.0 mL). After the solution was cooled to –78 °C, LDA (2.0 M in THF/heptane/ethylbenzene, 0.75 mL, 1.5 mmol, 1.5 equiv) was added to the Schlenk tube and the mixture was stirred at –78 °C for 30 min. The reaction mixture was treated with water (15 mL), and the resulting mixture was extracted with diethyl ether (20 mL) five times. The combined organic extracts were washed with water (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The yield of 3-bromopyrrole 17b was determined to be 98% by ¹H NMR spectroscopic analysis by using 1,1,2,2-tetrachloroethane (90.6 mg, 0.540 mmol) as an internal standard and comparing the relative values of integration for the peak observed at 6.30 ppm (one proton for 17b) with that of 1,1,2,2-tetrachloroethane observed at 5.96 ppm. The crude product was purified by silica gel column chromatography (hexane/diethyl ether, 3:2) to provide ethyl 3-bromo-1-(N,N-dimethylsulfamoyl)-1H-pyrrole-2-carboxylate (17b) as a colorless oil (238.9 mg, 0.873 mmol, 87%); R_f = 0.45 (hexane/diethyl ether, 1:1). IR (ATR): 1737, 1367, 1231, 1216, 1205, 722 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.21 (d, 1 H, J = 3.2 Hz), 6.30 (d, 1 H, J = 3.2 Hz), 4.38 (q, 2 H, J = 7.2 Hz), 2.97 (s, 6 H), 1.40 (t, 3 H, J = 7.2 Hz). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 159.9, 126.7, 123.8, 114.0, 106.7, 62.0, 38.6, 14.2. HRMS (DART/TOF): m/z [M + H]⁺ calcd for C₉H₁₄ ⁷⁹BrN₂O₄S: 324.9858; found: 324.9870.
• 15 CCDC 2205958, 2305930, 2205963, and 2153018 contain the supplementary crystallographic data for compounds 19a, 20a, 24a, and 31, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures
• 16 Typical procedure for in situ transmetalation; Ethyl 5-bromo-1-(N,N-dimethylsulfamoyl)-3-iodo-1H-pyrrole-2-carboxylate (19b): A flame-dried 50-mL Schlenk tube equipped with a Teflon-coated magnetic stirring bar and a rubber septum was charged with ethyl 5-bromo-1-(N,N-dimethylsulfamoyl)-1H-pyrrole-2-carboxylate (16b; 322.1 mg, 0.991 mmol, 1.0 equiv), ZnCl₂·TMEDA (305.4 mg, 1.21 mmol, 1.2 equiv), and THF (10.0 mL). After the solution was cooled to 0 °C, LDA (2.0 M in THF/heptane/ethylbenzene, 0.75 mL, 1.5 mmol, 1.5 equiv) was added to the Schlenk tube and the mixture was stirred for 30 min. The reaction mixture was treated with iodine (500.7 mg, 1.97 mmol, 2.0 equiv). After being stirred at 0 °C for 1 h, the reaction mixture was treated with saturated aqueous sodium thiosulfate (10 mL) and saturated aqueous ammonium chloride (10 mL). The mixture was partitioned and the aqueous layer was extracted with diethyl ether (20 mL) five times. The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a crude product. The yield of 3-iodopyrrole 19b was determined to be 90% by ¹H NMR spectroscopic analysis by using 1,1,2,2-tetrachloroethane (69.7 mg, 0.415 mmol) as an internal standard and comparing the relative values of integration for the peak observed at 6.44 ppm (one proton for 19b) with that of 1,1,2,2-tetrachloroethane observed at 5.96 ppm. The crude product was purified by silica gel column chromatography (hexane/diethyl ether, 4:1) to provide ethyl 5-bromo-1-(N,N-dimethylsulfamoyl)-3-iodo-1H-pyrrole-2-carboxylate (19b) as a pale yellow solid (333.0 mg, 0.738 mmol, 75%); R_f = 0.49 (hexane/CH₂Cl₂, 7:3); mp 56–57 °C. IR (ATR): 2972, 2922, 1728, 1453, 1390, 1227, 1183, 1155, 1046, 978, 725, 650 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.44 (s, 1 H), 4.38 (q, 2 H, J = 7.0 Hz), 3.07 (s, 6 H), 1.39 (t, 3 H, J = 7.0 Hz). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 161.3, 133.4, 123.3, 105.0, 68.6, 62.6, 38.6, 14.1. HRMS (DART/TOF): m/z [M + H]⁺ calcd for C₉H₁₃ ⁷⁹BrIN₂O₄S: 450.8824; found: 450.8827.
• 17 Mouri K, Saito S, Hisaki I, Yamaguchi S. Chem. Sci. 2013; 4: 4465
• 18 Synthesis of 23b: Bromopyrrole 23b was synthesized from 2-bromo-N,N-dimethyl-5-phenyl-1H-pyrrole-1-sulfonamide (22b; 325.0 mg, 0.987 mmol) according to the procedure for the halogen dance reaction. The yield of bromopyrrole 23b was determined to be quantitative by ¹H NMR spectroscopic analysis by using 1,1,2,2-tetrachloroethane (65.6 mg, 0.391 mmol) as an internal standard and comparing the relative values of integration for the peak observed at 2.43 ppm (six protons for 23b) with that of 1,1,2,2-tetrachloroethane observed at 5.96 ppm. Bromopyrrole 23b was obtained as a colorless solid (244.6 mg, 0.743 mmol, 75%); R_f = 0.49 (hexane/CH₂Cl₂, 1:1); mp 61–62 °C. IR (ATR): 1389, 1377, 1168, 1133, 1059, 986, 765, 730, 699 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.44 (m, 2 H), 7.41–7.36 (m, 3 H), 7.29 (d, 1 H, J = 2.2 Hz), 6.26 (d, 1 H, J = 2.2 Hz), 2.43 (s, 6 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 135.5, 131.0, 130.8, 128.9, 128.0, 123.7, 117.0, 98.8, 37.5. HRMS (DART/TOF): m/z [M + H]⁺ calcd for C₁₂H₁₄ ⁷⁹BrN₂O₂S: 328.9959; found: 328.9960.
• 19 Synthesis of 24b: Iodopyrrole 24b was synthesized from 2-bromo-N,N-dimethyl-5-phenyl-1H-pyrrole-1-sulfonamide (22b; 328.1 mg, 0.997 mmol) according to the procedure for in situ transmetalation. The yield of iodopyrrole 24b was determined to be 68% by ¹H NMR spectroscopic analysis by using 1,1,2,2-tetrachloroethane (51.0 mg, 0.304 mmol) as an internal standard and comparing the relative values of integration for the peak observed at 6.32 ppm (one proton for 24b) with that of 1,1,2,2-tetrachloroethane observed at 5.96 ppm. Iodopyrrole 24b was obtained as a colorless solid (249.5 mg, 0.548 mmol, 55%); R_f = 0.44 (hexane/CH₂Cl₂, 1:1); mp 97–98 °C. IR (ATR): 1394, 1174, 763, 738, 727, 651, 637 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.33 (m, 5 H), 6.32 (s, 1 H), 2.72 (s, 6 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 140.8, 132.5, 130.0, 128.5, 127.6, 121.3, 109.3, 76.7, 38.1. HRMS (DART/TOF): m/z [M + H]⁺ calcd for C₁₂H₁₃ ⁷⁹BrIN₂O₂S: 454.8926; found: 454.8903.
• 20a Otaegui D, Rodríguez-Gascón A, Zubia A, Cossío FP, Pedraz JL. Cancer Chemother. Pharmacol. 2009; 64: 153
• 20b Zubia A, Ropero S, Otaegui D, Ballestar E, Fraga MF, Boix-Chornet M, Berdasco M, Martinez A, Coll-Mulet L, Gil J, Cossío FP, Esteller M. Oncogene 2009; 28: 1477
• 21a Negishi E. Acc. Chem. Res. 1982; 15: 340
• 21b Negishi E.-I. Angew. Chem. Int. Ed. 2011; 50: 6738
• 22a Miyaura N, Yanagi T, Suzuki A. Synth. Commun. 1981; 11: 513
• 22b Miyaura N, Suzuki A. Chem. Rev. 1995; 95: 2457
• 23 Cossío FP, Esteller M, Zubia A, Otaegui D. WO Patent 074176, 2007